Ipilimumab: First results of a phase I trial in pediatric patients with advanced solid tumors.
9545 Background: Ipilimumab is a fully-human IgG1 monoclonal anti-CTLA-4 antibody which has been approved by the FDA for adult patients with metastatic melanoma . Although the approved dose is 3mg/kg every 21 days, the dose of 10mg/kg IV every 21 days for 4 doses in combination with chemotherapy was well tolerated in a phase III trial enrolling adult patients with melanoma. Methods: This pediatric phase I, dose escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of ipilimumab administered to patients <21yo with recurrent or progressive solid tumors. Ipilimumab was administered at 1, 3, 5, and 10mg/kg IV in a standard 3 + 3 design with 4 doses of induction therapy q3 weeks followed by maintenance q3 months until disease progression or unacceptable toxicity. Tumors were measured after 6 weeks, 12 weeks, and then every 3 months. Results: Twenty one patients (melanoma n=6, osteosarcoma n=6, soft tissue sarcomas n=7, neuroblastoma, and renal cell carcinoma) received a total of 57 doses of Ipilimumab to date. One of 6 patients treated at 5mg/kg developed a dose-limiting grade 3 pancreatitis. .At the highest dose level of 10mg/kg, two of three patients under 12yo developed DLT: grade 3 colitis and concurrent norovirus in one patient, and self-resolving grade 3 transaminitis in a second patient. Three of three patients between the ages of 12 and 21yo tolerated the 10mg/kg dosing schedule without DLT. Across all dose levels, grade 2 or 3 adverse events included colitis (n=1), transaminitis (n=3), pancreatitis (n=1), autoimmune thyroiditis (n=2), and hypophysitis (n=1) observed between C1D8 and C4D21. A single grade 1 rash was observed. Stable disease was the best response in 5 patients with a duration of 3 to 18 months. Conclusions: Ipilimumab can be safely administered to pediatric patients. Adolescents are able to tolerate the highest dose of 10mg/kg. Younger children (<12yo) had 2 DLTs in 3 patients at 10 mg/kg . Expansion of the 10 mg/kg cohort for adolescents and of the 5 mg/kg dose for the <12yo for further safety and pharmacokinetic information is underway. The spectrum of adverse events appears similar to those described in the adult trials, although there were no grade 2 or higher incidents of rash.